Neural network excitability is defined by the balance between excitation and inhibition. When this balance is disrupted in favor of excitation, networks become hyperexcitable. This observation constitutes a general guiding principle for determining the pathologies associated with epilepsy. With this in mind, significant effort has been directed towards understanding the molecular properties that define excitatory and inhibitory neurotransmission. A major source of inhibition in the brain results from the binding of the neurotransmitterY-aminobutyric acid (GABA) to GABAA receptor subtypes, which function as ligand-gated chloride channels. This GABAergic inhibition, in turn, depends on the chloride concentration gradient present across neuronal membranes. The CLC2 chloride channel subtype is one of several channels responsible for establishing this gradient. Recently, it was discovered that several human idiopathic generalized epilepsies (IGEs) are associated with CLC2 mutations. The thalamus, a subcortical structure, is a critical component for the generation of seizure activity associated with the IGEs. However, the function of CLC2 in the thalamus is unknown. The goal of my proposed project is to understand how CLC2 disruptions promote network hyperexcitability in the thalamus. My preliminary results indicate that CLC2 dysfunction enhances the excitability of thalamic network activity in vitro. This network enhancement is paralleled by a selective increase in synaptic excitation onto a subtype of thalamic neurons. While surprising to observe altered excitatory transmission during CLC2 disruption, this effect likely renders thalamic networks hyperexcitable. I have designed several experiments to determine the mechanism mediating this enhanced synaptic excitation. Several of these experiments rely on techniques - EEG recording/interpretation, local brain perfusion, imaging techniques - that I will learn from consultants that have agreed to train me.